Histone deacetylase is a metallodeacetylation enzyme having Zn in an active center (M. S. Finnin et al., Nature 401, 188–193 (1999)). This enzyme is considered to change affinity of various acetylated histones for DNA. The direct biological phenomenon brought about thereby is a structural change of chromatin. The minimum unit of chromatin structure is a nucleosome wherein 146 bp DNA is wound 1.8 times counterclockwise around a histone octamer (H2A, H2B, H3 and H4, each 2 molecules, core histone). The core histone stabilizes nucleosome structure by interaction of the positive charge of the N-terminal of each histone protein with DNA. The acetylation of histone is controlled by the balance between acetylation reaction, in which histone acetyltransferase is involved, and deacetylation, in which histone deacetylase is involved. The acetylation of histone occurs in a lysin residue of the N-terminal of histone protein that is evolutionally well preserved. Consequently, it is considered that the core histone protein loses electric charge of N-terminal, the interaction with DNA is attenuated and the nucleosomal structure becomes unstable. Therefore, deacetylation of histone is considered to bring about the opposite, or stabilization of nucleosomal structure. However, there are much to be clarified with regard to the degree of change of chromatin structure due to acetylation and the relationship thereof with the secondarily derived transcriptional control and the like.
On the other hand, a compound represented by the formula
(hereinafter to be also referred to as FR901228 substance) has been reported to derive a potent antitumor activity by selectively inhibiting histone deacetylase. Moreover, this substance causes high histone acetylation in treated cells, as a result of which it derives transcriptional control activity for various genes, cell cycle inhibitory activity and apoptosis inhibitory activity (JP-B-7-64872, H. Nakajima et al., Exp. Cell Res. 241, 126–166 (1998)). While there have heretofore been various reports on histone deacetylase inhibitors derived from naturally occurring substances, the FR901228 substance is a first pharmaceutical agent that has connected histone acetylation with biological phenomena expressed thereby, and whose clinical utility has been agreed on. The FR901228 substance has a disulfide bond in a molecule.
It is an object of the present invention to provide a compound having a stronger histone deacetylase inhibitory activity and a histone deacetylase inhibitor comprising the compound. Another object of the present invention is to provide use of the compound having a histone deacetylase inhibitory activity as a pharmaceutical agent.